Thursday, March 23, 2017

Mantle-cell lymphoma neoantigens are derived from immunoglobulins

This week Nature published new study that could explain why B cell-derived lymphomas are not easily rejected by body's immune system. It also highlights some of the obvious forgetfulness regarding basic immunology concepts.

In this paper, research group from Stanford analyzed neo-antigenic burden in untreated mantle-cell lymphoma, a subtype of B-cell non-Hodgkin lymphoma. Rather than simply doing whole exome-sequencing of lymphoma DNA to identify tumor associated non-synonymous somatic mutations, the authors focused on direct proteomic analysis of cancer MHC ligands, epitopes, by liquid chromatography and tandem mass spectrometry (LC–MS/MS).

Interestingly, though the authors found 13–175 non-synonymous somatic mutations per patient within genes known to mutate in mantle-cell lymphoma, such as TP53, CCND1, none of the mutated neo-epitopes from these genes were actually presented by MHC molecules. Only exception were neo-antigens derived from immunoglobulin (Ig) genes themselves. Surprise, surprise!

As the authors wrote "presentation of variable-region peptides by MHC-II suggests that Ig neoantigen recognition by CD4 does not inhibit lymphoma development." Why that could be the case? As we know, when B cell responds to antigen it undergoes hypermutations within its Ig variable regions. In essence, every responding B cell generates neo-antigens within its Ig molecules. These are antibodies the body is using to defend against pathogens. Obviously Ig hypermutated B cells (and memory B cells or plasma cells derived from such B cells) are not ordinarily rejected by body's own immune system. It is strange that the authors did not mention this obvious contradiction.